Mutated in Autosomal Dominant Proximal Arthrogryposis.

Objectives: The main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis.

Methods: We performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing.

Results: A 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in in the family.

Discussion: The altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of in the disease.